Letters
Author Affiliations: Wright Foundation for Pediatric Ophthalmology and Strabismus, Los Angeles, California; Cedars-Sinai Medical Center, Los Angeles, California; Keck School of Medicine, University of Southern California, Los Angeles. Corresponding Author: Kenneth W. Wright, MD, Wright Foundation for Pediatric Ophthalmology and Strabismus, 520 S San Vicente Blvd, Los Angeles, CA 90048 ([email protected]). Published Online: October 30, 2014. doi:10.1001/jamaophthalmol.2014.4259. Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Chaudhuri Z, Demer JL. Surgical outcomes following rectus muscle plication: a potentially reversible, vessel-sparing alternative to resection. JAMA Ophthalmol. 2014;132(5):579-585. 2. Wright KW. Rectus strengthening procedures. In: Wright KW, ed. Color Atlas of Ophthalmic Surgery: Strabismus. Philadelphia, PA: Lippincott; 1991. 3. Wright KW, Lanier AB. Effect of a modified rectus tuck on anterior segment circulation in monkeys. J Pediatr Ophthalmol Strabismus. 1991;28(2):77-81.
In Reply We thank Dr Wright for his interest in our recent report of surgical outcomes of rectus plication, a comparatively ancient surgical technique deserving reconsideration after having fallen out of favor in the Americas for historical reasons. Tucking and plication are synonymous terms. Plication of rectus extraocular muscles (EOMs) was reported as early as 1883. 1 Reported modifications have included muscle-tomuscle tucking and anterior and posterior suturing to the scleral bed.2 Problems associated with anterior muscle-tomuscle plication may include eventual relaxation of the imbrication and real or anticipated cosmetic blemish putatively produced by the anterior bulk of the advanced EOM. We do not advocate muscle-to-muscle rectus plication. Instead, posterior muscle-to-sclera plication, described in our recent article, has the advantage of folding the plicated tissue between the posterior EOM and sclera and avoids cosmetic blemish.3 Our experience identified no cosmetic disadvantage to plication. We agree with Dr Wright that plication’s effect is due to EOM shortening. Because EOMs are elastic, shortening necessarily increases elastic tension, which is probably the only immediate way that EOM force can be increased surgically. We therefore think that Dr Wright’s distinction between “strengthening” and “tightening” operations is merely semantic for most strabismus surgery that is not intended to restrict duction. The plicated portion of an EOM becomes mechanically inactive, although traversing ciliary vessels are not deliberately sacrificed as inherent in resection. Therefore, EOM resection and plication are biomechanically indistinguishable. Dr Wright asserts that “A plication of the right medial rectus muscle causes slight limitation of abduction, thus inducing an eso shift in right gaze and having little effect in left gaze.” We have not observed such a phenomenon. Moreover, biomechanical analysis suggests that Dr Wright’s assertion is incorrect for typical horizontal strabismus. For example, computational simulation4 of 30–prism diopter (PD) concomitant exotropia treated by 4-mm shortening (plication or resection) of the right medial rectus muscle indicates similar surgical reduction of exotropia to 15 PD in central gaze, 20 PD in 30° dextroversion, and 18 PD in 30° levoversion; the incomitance is inconsistent or clinically negligible. jamaophthalmology.com
Plication supplanted resection in much of Europe in the 1980s and 1990s.2 Our recent article acknowledged Dr Wright’s 1991 iris angiographic study in cynomolgous monkeys demonstrating preservation of ciliary circulation after anterior (surface) EOM plication as advocated by Dr Wright.5 Dr Wright’s letter questioned whether our technique of posterior plication might compromise anterior ciliary circulation, despite our intrasurgical observations that ciliary arteries appear to remain patent. A recent iris angiographic study in humans following posterior plication, resection, and recession operations of rectus EOMs is reassuring in this regard.6 Anterior segment circulation was angiographically preserved after posterior plication was performed as we described. Therefore, we continue to maintain that muscle-to-sclera posterior plication not only is a quick, effective, and minimally traumatic procedure for EOM tightening but also spares ciliary circulation. Zia Chaudhuri, MS, FRCS(Glasg) Joseph L. Demer, MD, PhD Author Affiliations: Lady Hardinge Medical College and Associated Hospitals, New Delhi, India (Chaudhuri); Postgraduate Institute of Medical Education and Research, New Delhi, India (Chaudhuri); Dr Ram Manohar Lohia Hospital, New Delhi, India (Chaudhuri); Stein Eye Institute, University of California, Los Angeles (Demer). Corresponding Author: Joseph L. Demer, MD, PhD, Stein Eye Institute, University of California, Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095 ([email protected]). Published Online: October 30, 2014. doi:10.1001/jamaophthalmol.2014.4263. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Chaudhuri reported having received a grant from the National Eye Institute and the Better Opportunities for Young Scientists in Chosen Areas of Science & Technology Fellowship of the Government of India. Dr Demer reported having received a grant from the National Eye Institute. No other disclosures were reported. 1. Roth A, Speeg-Schatz C. Muscle plication. In: Roth A, Speeg-Schatz C. Eye Muscle Surgery: Basic Data, Operative Techniques, Surgical Strategy. Lisse, the Netherlands: Swets & Zeitlinger; 2001:171-172. 2. Hamtil LW. A study in tucking extraocular muscles to correct strabismus. Ann Ophthalmol. 1983;15(2):136-137. 3. Rüssmann W. Surgical treatment of squint today: a status determination [in German]. Fortschr Ophthalmol. 1990;87(suppl):S155-S162. 4. Miller JM, Pavlovski DS, Shaemeva I. Orbit 1.8 Gaze Mechanics Simulation. San Francisco, CA: Eidactics; 1999. 5. Wright KW, Lanier AB. Effect of a modified rectus tuck on anterior segment circulation in monkeys. J Pediatr Ophthalmol Strabismus. 1991;28(2):77-81. 6. Oltra EZ, Pineles SL, Demer JL, Quan AV, Velez FG. The effect of rectus muscle recession, resection, and plication on anterior segment circulation in humans. Paper presented at: 40th Annual Meeting of the American Association of Pediatric Ophthalmology and Strabismus; April 5, 2014; Palm Springs, CA.
Reperfusion of Areas of Ischemia in Central Retinal Vein Occlusion To the Editor We read with interest the article by Kamei et al1 reporting reperfusion of ischemic regions of the retina in 2 patients with central retinal vein occlusion (CRVO). The reperfusion illustrated by the authors is quite impressive, and we look forward to larger studies on the efficacy of activated protein C in patients with ischemic CRVO. In their article, Kamei and colleagues mentioned that “reperfusion in ischemic CRVO has not been reported previously.”1 (Reprinted) JAMA Ophthalmology February 2015 Volume 133, Number 2
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227
Letters
Although it is true that some earlier studies have reported either no change or increases in the areas of retinal nonperfusion (RNP),2,3 others have reported decreases in areas of RNP in some patients with CRVO or branch retinal vein occlusion.4,5 A study by Campochiaro et al4 reported that reperfusion of nonperfused retina was observed in 6% to 8% of patients with CRVO who were treated with intravitreal ranibizumab injections, compared with only 1% of sham-treated patients. Furthermore, the proportion of patients with no RNP at 6 months was higher in the groups treated with ranibizumab (0.3 mg, 82.0%; 0.5 mg, 84%) compared with the sham group (67.0%). In a study by Terui et al,5 4 of 21 eyes (19.0%) with areas of capillary nonperfusion at baseline experienced decreases in the area of capillary nonperfusion larger than 1 disc area (DA) after treatment with intravitreal bevacizumab. The mechanism by which reperfusion occurs following treatment with intravitreal anti–vascular endothelial growth factor (VEGF) agents remains uncertain. Campochiaro et al4 suggested that VEGF exacerbates retinal ischemia by increasing leukostasis. Intravitreal anti-VEGF agents may break this feedback loop, thereby allowing reperfusion to occur. The effects of activated protein C reported by Kamei and colleagues offer another promising modality of treatment for patients with ischemic CRVO. In summary, changes in the areas of capillary nonperfusion and especially reperfusion of ischemic areas may occur in patients with CRVO following treatment with anti-VEGF agents or, as reported,1 activated protein C. This suggests that the extent of capillary nonperfusion may not be static in ischemic CRVO and raises questions on the most appropriate time and extent of laser photocoagulation for treatment of ischemic regions in CRVO. Colin S. Tan, FRCSEd(Ophth) Milton C. Chew, MBBS SriniVas R. Sadda, MD Author Affiliations: National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore (Tan, Chew); Doheny Eye Institute, University of Southern California, Los Angeles (Sadda). Corresponding Author: SriniVas R. Sadda, MD, Doheny Eye Institute, DEI 3623, University of Southern California, 1450 San Pablo St, Los Angeles, CA 90033 ([email protected]). Published Online: November 6, 2014. doi:10.1001/jamaophthalmol.2014.4245. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Tan reported receiving travel support from Bayer. Dr Sadda reported having previously shared in royalties from intellectual property licensed to Topcon Medical Systems by the Doheny Eye Institute, having previously served on the scientific advisory board for Heidelberg Engineering, and receiving research support from Carl Zeiss Meditec, Optovue Inc, and Optos. No other disclosures were reported. Funding/Support: This work was supported in part by grant EY03040 from the National Institutes of Health (Dr Sadda), grant R01 EY014375 from the National Eye Institute (Dr Sadda), and Clinician Scientist Career Scheme Grant CSCS/12005 and Clinician Leadership in Research Grant CLR-09006 from the National Healthcare Group (Dr Tan). Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 228
1. Kamei M, Matsumura N, Suzuki M, Sakimoto S, Sakaguchi H, Nishida K. Reperfusion of large ischemic areas associated with central retinal vein occlusion: a potential novel treatment with activated protein C. JAMA Ophthalmol. 2014;132(3):361-362. 2. Sophie R, Hafiz G, Scott AW, et al. Long-term outcomes in ranibizumabtreated patients with retinal vein occlusion: the role of progression of retinal nonperfusion. Am J Ophthalmol. 2013;156(4):693-705. 3. Sadda S, Danis RP, Pappuru RR, et al. Vascular changes in eyes treated with dexamethasone intravitreal implant for macular edema after retinal vein occlusion. Ophthalmology. 2013;120(7):1423-1431. 4. Campochiaro PA, Bhisitkul RB, Shapiro H, Rubio RG. Vascular endothelial growth factor promotes progressive retinal nonperfusion in patients with retinal vein occlusion. Ophthalmology. 2013;120(4):795-802. 5. Terui T, Kondo M, Sugita T, et al. Changes in areas of capillary nonperfusion after intravitreal injection of bevacizumab in eyes with branch retinal vein occlusion. Retina. 2011;31(6):1068-1074.
In Reply The summary by Tan and colleagues that the extent of capillary nonperfusion may not be static in ischemic CRVO complements the findings of our study.1 Tan and colleagues pointed out that some studies have reported decreases in areas of nonperfusion in some patients with retinal vein occlusion.2,3 We agree that the study by Campochiaro et al2 mentioned that reperfusion of areas of RNP occurred at a 6- to 8-fold higher rate (6% or 8%) in patients treated with anti-VEGF drugs compared with patients who received sham treatment (1%), which is consistent with our finding that reperfusion of ischemic areas can occur in patients with CRVO after treatment. However, there seem to be slight differences of opinion. The difference between our study and the study by Campochiaro and colleagues is an area of reperfusion; we found reperfusion of large ischemic areas in severe ischemic cases of CRVO, while very few patients with the ischemic type of CRVO were included in their study. The number of patients with more than 5 or 10 DAs of RNP (0-3 patients) did not change significantly over 12 months in their study. Furthermore, most patients with CRVO (about 80%) had no baseline RNP and 12.3% had between 0 and 1 DA of RNP. Therefore, in their study, if reperfusion developed, it was limited to a very small area (perhaps
Author Affiliations: Wright Foundation for Pediatric Ophthalmology and Strabismus, Los Angeles, California; Cedars-Sinai Medical Center, Los Angeles, California; Keck School of Medicine, University of Southern California, Los Angeles. Corresponding Author: Kenneth W. Wright, MD, Wright Foundation for Pediatric Ophthalmology and Strabismus, 520 S San Vicente Blvd, Los Angeles, CA 90048 ([email protected]). Published Online: October 30, 2014. doi:10.1001/jamaophthalmol.2014.4259. Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Chaudhuri Z, Demer JL. Surgical outcomes following rectus muscle plication: a potentially reversible, vessel-sparing alternative to resection. JAMA Ophthalmol. 2014;132(5):579-585. 2. Wright KW. Rectus strengthening procedures. In: Wright KW, ed. Color Atlas of Ophthalmic Surgery: Strabismus. Philadelphia, PA: Lippincott; 1991. 3. Wright KW, Lanier AB. Effect of a modified rectus tuck on anterior segment circulation in monkeys. J Pediatr Ophthalmol Strabismus. 1991;28(2):77-81.
In Reply We thank Dr Wright for his interest in our recent report of surgical outcomes of rectus plication, a comparatively ancient surgical technique deserving reconsideration after having fallen out of favor in the Americas for historical reasons. Tucking and plication are synonymous terms. Plication of rectus extraocular muscles (EOMs) was reported as early as 1883. 1 Reported modifications have included muscle-tomuscle tucking and anterior and posterior suturing to the scleral bed.2 Problems associated with anterior muscle-tomuscle plication may include eventual relaxation of the imbrication and real or anticipated cosmetic blemish putatively produced by the anterior bulk of the advanced EOM. We do not advocate muscle-to-muscle rectus plication. Instead, posterior muscle-to-sclera plication, described in our recent article, has the advantage of folding the plicated tissue between the posterior EOM and sclera and avoids cosmetic blemish.3 Our experience identified no cosmetic disadvantage to plication. We agree with Dr Wright that plication’s effect is due to EOM shortening. Because EOMs are elastic, shortening necessarily increases elastic tension, which is probably the only immediate way that EOM force can be increased surgically. We therefore think that Dr Wright’s distinction between “strengthening” and “tightening” operations is merely semantic for most strabismus surgery that is not intended to restrict duction. The plicated portion of an EOM becomes mechanically inactive, although traversing ciliary vessels are not deliberately sacrificed as inherent in resection. Therefore, EOM resection and plication are biomechanically indistinguishable. Dr Wright asserts that “A plication of the right medial rectus muscle causes slight limitation of abduction, thus inducing an eso shift in right gaze and having little effect in left gaze.” We have not observed such a phenomenon. Moreover, biomechanical analysis suggests that Dr Wright’s assertion is incorrect for typical horizontal strabismus. For example, computational simulation4 of 30–prism diopter (PD) concomitant exotropia treated by 4-mm shortening (plication or resection) of the right medial rectus muscle indicates similar surgical reduction of exotropia to 15 PD in central gaze, 20 PD in 30° dextroversion, and 18 PD in 30° levoversion; the incomitance is inconsistent or clinically negligible. jamaophthalmology.com
Plication supplanted resection in much of Europe in the 1980s and 1990s.2 Our recent article acknowledged Dr Wright’s 1991 iris angiographic study in cynomolgous monkeys demonstrating preservation of ciliary circulation after anterior (surface) EOM plication as advocated by Dr Wright.5 Dr Wright’s letter questioned whether our technique of posterior plication might compromise anterior ciliary circulation, despite our intrasurgical observations that ciliary arteries appear to remain patent. A recent iris angiographic study in humans following posterior plication, resection, and recession operations of rectus EOMs is reassuring in this regard.6 Anterior segment circulation was angiographically preserved after posterior plication was performed as we described. Therefore, we continue to maintain that muscle-to-sclera posterior plication not only is a quick, effective, and minimally traumatic procedure for EOM tightening but also spares ciliary circulation. Zia Chaudhuri, MS, FRCS(Glasg) Joseph L. Demer, MD, PhD Author Affiliations: Lady Hardinge Medical College and Associated Hospitals, New Delhi, India (Chaudhuri); Postgraduate Institute of Medical Education and Research, New Delhi, India (Chaudhuri); Dr Ram Manohar Lohia Hospital, New Delhi, India (Chaudhuri); Stein Eye Institute, University of California, Los Angeles (Demer). Corresponding Author: Joseph L. Demer, MD, PhD, Stein Eye Institute, University of California, Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095 ([email protected]). Published Online: October 30, 2014. doi:10.1001/jamaophthalmol.2014.4263. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Chaudhuri reported having received a grant from the National Eye Institute and the Better Opportunities for Young Scientists in Chosen Areas of Science & Technology Fellowship of the Government of India. Dr Demer reported having received a grant from the National Eye Institute. No other disclosures were reported. 1. Roth A, Speeg-Schatz C. Muscle plication. In: Roth A, Speeg-Schatz C. Eye Muscle Surgery: Basic Data, Operative Techniques, Surgical Strategy. Lisse, the Netherlands: Swets & Zeitlinger; 2001:171-172. 2. Hamtil LW. A study in tucking extraocular muscles to correct strabismus. Ann Ophthalmol. 1983;15(2):136-137. 3. Rüssmann W. Surgical treatment of squint today: a status determination [in German]. Fortschr Ophthalmol. 1990;87(suppl):S155-S162. 4. Miller JM, Pavlovski DS, Shaemeva I. Orbit 1.8 Gaze Mechanics Simulation. San Francisco, CA: Eidactics; 1999. 5. Wright KW, Lanier AB. Effect of a modified rectus tuck on anterior segment circulation in monkeys. J Pediatr Ophthalmol Strabismus. 1991;28(2):77-81. 6. Oltra EZ, Pineles SL, Demer JL, Quan AV, Velez FG. The effect of rectus muscle recession, resection, and plication on anterior segment circulation in humans. Paper presented at: 40th Annual Meeting of the American Association of Pediatric Ophthalmology and Strabismus; April 5, 2014; Palm Springs, CA.
Reperfusion of Areas of Ischemia in Central Retinal Vein Occlusion To the Editor We read with interest the article by Kamei et al1 reporting reperfusion of ischemic regions of the retina in 2 patients with central retinal vein occlusion (CRVO). The reperfusion illustrated by the authors is quite impressive, and we look forward to larger studies on the efficacy of activated protein C in patients with ischemic CRVO. In their article, Kamei and colleagues mentioned that “reperfusion in ischemic CRVO has not been reported previously.”1 (Reprinted) JAMA Ophthalmology February 2015 Volume 133, Number 2
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a Purdue University User on 05/19/2015
227
Letters
Although it is true that some earlier studies have reported either no change or increases in the areas of retinal nonperfusion (RNP),2,3 others have reported decreases in areas of RNP in some patients with CRVO or branch retinal vein occlusion.4,5 A study by Campochiaro et al4 reported that reperfusion of nonperfused retina was observed in 6% to 8% of patients with CRVO who were treated with intravitreal ranibizumab injections, compared with only 1% of sham-treated patients. Furthermore, the proportion of patients with no RNP at 6 months was higher in the groups treated with ranibizumab (0.3 mg, 82.0%; 0.5 mg, 84%) compared with the sham group (67.0%). In a study by Terui et al,5 4 of 21 eyes (19.0%) with areas of capillary nonperfusion at baseline experienced decreases in the area of capillary nonperfusion larger than 1 disc area (DA) after treatment with intravitreal bevacizumab. The mechanism by which reperfusion occurs following treatment with intravitreal anti–vascular endothelial growth factor (VEGF) agents remains uncertain. Campochiaro et al4 suggested that VEGF exacerbates retinal ischemia by increasing leukostasis. Intravitreal anti-VEGF agents may break this feedback loop, thereby allowing reperfusion to occur. The effects of activated protein C reported by Kamei and colleagues offer another promising modality of treatment for patients with ischemic CRVO. In summary, changes in the areas of capillary nonperfusion and especially reperfusion of ischemic areas may occur in patients with CRVO following treatment with anti-VEGF agents or, as reported,1 activated protein C. This suggests that the extent of capillary nonperfusion may not be static in ischemic CRVO and raises questions on the most appropriate time and extent of laser photocoagulation for treatment of ischemic regions in CRVO. Colin S. Tan, FRCSEd(Ophth) Milton C. Chew, MBBS SriniVas R. Sadda, MD Author Affiliations: National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore (Tan, Chew); Doheny Eye Institute, University of Southern California, Los Angeles (Sadda). Corresponding Author: SriniVas R. Sadda, MD, Doheny Eye Institute, DEI 3623, University of Southern California, 1450 San Pablo St, Los Angeles, CA 90033 ([email protected]). Published Online: November 6, 2014. doi:10.1001/jamaophthalmol.2014.4245. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Tan reported receiving travel support from Bayer. Dr Sadda reported having previously shared in royalties from intellectual property licensed to Topcon Medical Systems by the Doheny Eye Institute, having previously served on the scientific advisory board for Heidelberg Engineering, and receiving research support from Carl Zeiss Meditec, Optovue Inc, and Optos. No other disclosures were reported. Funding/Support: This work was supported in part by grant EY03040 from the National Institutes of Health (Dr Sadda), grant R01 EY014375 from the National Eye Institute (Dr Sadda), and Clinician Scientist Career Scheme Grant CSCS/12005 and Clinician Leadership in Research Grant CLR-09006 from the National Healthcare Group (Dr Tan). Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 228
1. Kamei M, Matsumura N, Suzuki M, Sakimoto S, Sakaguchi H, Nishida K. Reperfusion of large ischemic areas associated with central retinal vein occlusion: a potential novel treatment with activated protein C. JAMA Ophthalmol. 2014;132(3):361-362. 2. Sophie R, Hafiz G, Scott AW, et al. Long-term outcomes in ranibizumabtreated patients with retinal vein occlusion: the role of progression of retinal nonperfusion. Am J Ophthalmol. 2013;156(4):693-705. 3. Sadda S, Danis RP, Pappuru RR, et al. Vascular changes in eyes treated with dexamethasone intravitreal implant for macular edema after retinal vein occlusion. Ophthalmology. 2013;120(7):1423-1431. 4. Campochiaro PA, Bhisitkul RB, Shapiro H, Rubio RG. Vascular endothelial growth factor promotes progressive retinal nonperfusion in patients with retinal vein occlusion. Ophthalmology. 2013;120(4):795-802. 5. Terui T, Kondo M, Sugita T, et al. Changes in areas of capillary nonperfusion after intravitreal injection of bevacizumab in eyes with branch retinal vein occlusion. Retina. 2011;31(6):1068-1074.
In Reply The summary by Tan and colleagues that the extent of capillary nonperfusion may not be static in ischemic CRVO complements the findings of our study.1 Tan and colleagues pointed out that some studies have reported decreases in areas of nonperfusion in some patients with retinal vein occlusion.2,3 We agree that the study by Campochiaro et al2 mentioned that reperfusion of areas of RNP occurred at a 6- to 8-fold higher rate (6% or 8%) in patients treated with anti-VEGF drugs compared with patients who received sham treatment (1%), which is consistent with our finding that reperfusion of ischemic areas can occur in patients with CRVO after treatment. However, there seem to be slight differences of opinion. The difference between our study and the study by Campochiaro and colleagues is an area of reperfusion; we found reperfusion of large ischemic areas in severe ischemic cases of CRVO, while very few patients with the ischemic type of CRVO were included in their study. The number of patients with more than 5 or 10 DAs of RNP (0-3 patients) did not change significantly over 12 months in their study. Furthermore, most patients with CRVO (about 80%) had no baseline RNP and 12.3% had between 0 and 1 DA of RNP. Therefore, in their study, if reperfusion developed, it was limited to a very small area (perhaps
